Nocturnal wheezing is an important feature of asthma. For many patients, nighttime exacerbations of asthma are frequent and often serious. Yet to be determined, however, are the mechanisms that cause nocturnal asthma. The goal of this proposal is to establish the causes of sleep-related airflow obstructions and the critical factors which are involved in this process. To achieve this goal, evidence has been obtained that circadian variations(epinephrine and, possibly, cortisol) and sleep are important factors for nighttime airflow obstruction and airway inflammation. Therefore, it is hypothesized that a mechanism of nocturnal asthma is the circadian fall in epinephrine and cortisol which promotes airway inflammation through the release or generation of cytokines. Furthermore, it is hypothesized that sleep is an independent contributor to this process but also through enhanced release of pro- inflammatory cytokines. Specific aims of this proposal are designed to determine the separate contributions of circadian patterns (epinephrine and cortisol) and sleep to nocturnal asthma. To accomplish these goals, asthma patients will be studied on four different hospitalized (General Clinical Research Unit) occasions. The four study periods are designed to determine the individual, and potentially interactive, influences of circadian rhythms (as measured by plasma epinephrine and cortisol) and sleep on pulmonary physiology, airway inflammation and airway and blood cell function. The effect of these variables on pulmonary physiology will be confirmed by spirometry. In addition, bronchoalveolar lavage (BAL) will be performed on each study occasion. BAL fluid will be used to quantitate airway inflammation by cell counts, lymphocyte markers(e.g. CD4, CD8, CD25), mediators (histamine and tryptase) and protein. Airway cell function, e.g. generation of superoxide, presence of eosinophil granular proteins (representing activation and release), concentrations of cytokines (IL-1, IL-4, IL-5, GM-CSF, TNF-alpha, and INF-gamma), and expression of mRNA for these cytokines, will be measured. Furthermore, to ascertain whether changes in cell function in nocturnal asthma are compartmentalized to the airway, peripheral blood cells will be used for lymphocytes surface markers, lymphocyte release and expression of cytokine mRNA, and eosinophil generation of superoxide. The independent, and interactive, influences of circadian patterns and sleep to changes in physiology, inflammation and cell function will then be determined. These observations, will provide new information on the mechanisms of nocturnal asthma and insight into regulation of pulmonary inflammation.